1. Technical Field
The present invention relates generally to the fields of molecular biology and inflammation. More specifically, the present invention relates to the identification of novel variants of CD38 and uses thereof.
2. Background Information
T-lymphocytes bearing the CD4 receptor (CD4+), called CD4+ T cells, augment the immune response by secreting cytokines that stimulate either a cytotoxic T cell response (T-helper 1) or an antibody response (T-helper 2). Naïve CD4+ T cells can differentiate to Th1 or Th2 cells after the engagement of TCR-peptide-MHC class II complex, depending on the existing cytokines in the environment. Thus, CD4+ T cells play critical roles in T cell-mediated immune responses. Novel genes that function in T cell activation may provide novel drug targets for autoimmune and inflammatory disease. Accordingly, the identification and characterization of novel genes which are involved in the activation of CD4+ T cells is considered important.
CD38 is a multifunctional cell surface antigen that functions in cell adhesion, signal transduction and calcium signaling. CD38 catalyzes the production of cyclic ADP-ribose (cADPR) from its substrate NAD+. Takasawa, S. Et al. (1993) J. Biol. Chem. 268: 26052-26054. cADPR acts as a second messenger that regulates intracellular calcium release. CD38 is expressed in hematopoeitic cells including T lymphocytes, B lymphocytes and neutrophils. CD38−/− mice shows a complete loss of tissue-associated NAD+ glycohydrolase activity and exhibited marked deficiencies in antibody responses to T cell-dependent protein antigens. Cockayne, et al. (1998) Blood 92: 1324-1333. CD38 controls neutrophil chemotaxis to bacterial chemoattractants through its production of cyclic ADP-ribose, and acts as a critical regulator of inflammation and innate immune responses. Partida-Sanchez S, et al. (2002) Nat Med 7:1209-16. The human cDNA of CD38 was first cloned in 1990 and it encodes 300 amino acids. Jackson, D. G.; Bell, J. I. (1990) J. Immun. 144: 2811-2815. It was reported that the CD38 gene is present in a single copy and extends over more than 62 kb. It consists of 8 exons and 7 introns, including a long intron that interrupts the 5-prime coding region. Ferrero, E.; Malavasi, F. (1997) J. Immun. 159: 3858-3865. The structure of the CD38 protein is unknown.
Cell surface antigens like CD38 have been known to occur in different isoforms that are structurally and functionally different from one another. For example CXCR-3 has two isoforms, CXCR3A and CXCR3-B, that have been found to have different biological activities and to trigger different signal transduction pathways. CXCR3-B shows high affinity only for CXCL4 where CXR3-A does not. Lasagni L et al, J Exp Med. 2003, 197:1537-49).
One cDNA splicing isoform of CD38, which only encodes 122 amino acid residues, was isolated from a human testis library. (Nata, K. et al, 1997, Gene 186, 285292).
The discovery of a new isoform for CD38 and the polynucleotides encoding it satisfies a need in the art by providing new compositions which may be used in the treatment, prevention and diagnosis of autoimmune and immunological diseases.